This invention relates to diagnosing Alzheimer's disease.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder which is characterized by memory loss, impairment in abstract thinking, impaired judgment, personality change, and insidious onset of the disease in the absence of other specific causes of dementia. Eventually, the AD patient becomes completely incapacitated, and death results from debilitation or infection.
Under the guidelines established by the National Institute of Neurological and Communicative Disorders and Stroke, and the Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA), a clinical diagnosis of probable AD involves the administration of a series of neuropsychologic tests (see Table 1). Many of the signs of AD occur as part of the normal process of aging or may result from other forms of dementia, and thus the present NINCDS/ADRDA standards require the absence of an alternative explanation for the symptoms.
Table 1: NINCDS/ADRDA Criteria for Clinical Diagnosis of Alzheimer's Disease
Criteria for the clinical diagnosis of probable Alzheimer's disease include
Dementia established by clinical examination and documented by the Mini-Mental State Examination, Blessed Dementia Scale, or some similar examination and confirmed by neuropsychologic tests PA1 Deficits in two or more area of cognition PA1 Progressive worsening of memory and other cognitive functions PA1 No disturbance of consciousness PA1 Onset between ages 40 and 90, most often after age 65 PA1 Absence of systemic disorders or other brain diseases that could account for the progressive deficits in memory and cognition PA1 Progressive deterioration of specific cognitive functions such as language (aphasia), motor skills (apraxia), and perception (agnosia) PA1 Impaired activities of daily living and altered patterns of behavior PA1 Family history of similar disorders, particularly if confirmed neuropathologically PA1 Laboratory results as follows: normal puncture as evaluated by standard techniques; normal pattern or nonspecific changes in EEG, such as increased slow-wave activity; and evidence of cerebral atrophy of CT with progression documented by serial observation PA1 Plateaus in the course of progression of the illness PA1 Associated system of depression, insomnia, incontinence, delusions, illusions, hallucinations, sexual disorders, weight loss, and catastrophic verbal, emotional, or physical outbursts PA1 Seizures in advanced disease PA1 CT normal for age PA1 Sudden, apoplectic onset PA1 Focal neurologic finds such as hemiparesis, sensory loss, visual field deficits, and incoordination early in the course of the illness PA1 Seizures or gait disturbances at the onset or very early in the course of the illness PA1 May be made on the basis of the dementia syndrome, in the absence of other neurologic, psychiatric, or systemic disorders sufficient to cause dementia and in the presence of variations in the onset, presentation, or clinical course PA1 May be made in the presence of a second systemic or brain disorder sufficient to produce dementia, which is not considered to be the cause of the dementia PA1 Should be used in research studies when a single, gradually progressive, severe cognitive deficit is identified in the absence of another identifiable cause PA1 The clinical criteria for probable Alzheimer's disease PA1 Histopathologic evidence obtained from a biopsy or autopsy PA1 Familial occurrence PA1 Onset before age 65 PA1 Presence of trisomy 21 PA1 Coexistence of other relevant conditions, such as Parkinson's disease
The diagnosis of probable Alzheimer's disease is supported by
Other clinical features consistent with the diagnosis of probable Alzheimer's disease, after exclusion of causes of dementia other than Alzheimer's disease, include
Other neurologic abnormalities in some patients, especially with more advance disease and including motor signs such as increased muscle tone, myocionus, or gait disorder
Features that make the diagnosis of probable Alzheimer's disease uncertain or unlikely include
Clinical diagnosis of possible Alzheimer's disease
Criteria for diagnosis of definite Alzheimer's disease are
Classification of Alzheimer's disease for research purposes should specify features that may differentiate subtype of the disorder, such as
Note: NINCDS=National Institute of Neurological and Communicative Disorders and Stroke; ADRDA=Alzheimer's Disease and Related Disorders Association
Under the current standards established by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), a post-mortem diagnosis of definite AD involves a series of histopathologic test on biological samples obtained from the patient. Tables 2 and 3 indicate that the CERAD neuropathologic diagnosis is derived from an evaluation of senile plague frequency and a clinical history of dementia.
TABLE 2 ______________________________________ Age-related plaque scores* Age of patient at Frequency of plaques.sup.+ death (yrs) None Sparse Moderate Frequent ______________________________________ &lt;50 O C C C 50-75 O B C C &gt;75 O A B C ______________________________________ *An agerelated plaque score is determined using patient's age along with plaque frequency in the most heavily affected neocortical section. .sup.+ Based on section of frontal, temporal, or parietal cortex with maximum involvement. For purpose of this protocol, the letter circled corresponds to the following assessment: O = NO histologic evidence of Alzheimer's disease. A = Histologic findings are UNCERTAIN evidence of Alzheimer's disease. B = Histologic findings SUGGEST the diagnosis of Alzheimer's disease. C = Histologic findings INDICATE the diagnosis of Alzheimer's disease.
TABLE 3 ______________________________________ Neuropathology diagnosis: Diagnostic criteria for Alzheimer's disease ______________________________________ Normal (with respect to AD a. No histologic evidence of or other dementing Alzheimer's disease (0 score), and no processes clinical history of dementia, and (choose one) absence of other neuropathologic lesions likely to cause dementia b. An "A" age-related plaque score and no clinical history of dementia c. A history of dementia and absence of any neuropathologic lesions likely to cause dementia Definite "C" age-related plaque score, and clinical history of dementia, and presence or absence of other neuropathologic lesions likely to cause dementia CERAD NP probable* "B" age-related plaque score, and clinical history of dementia, and presence or absence of other neuropathologic disorders likely to cause dementia CERAD NP possible* a. "A" age-related plaque score, and (choose one) clinical history of dementia, and presence or absence of other neuropathologic lesions that could cause dementia b. "B" or "C" age-related plaque score and absence of clinical manifestations of dementia ______________________________________ *Not to be confused with the NINCDSADRDA clinical criteria (McKhann et al., Neurology 1984; 34:939-944). The agerelated plaque score is integrated with the presence or absence of a clinical history of dementia to arrive at a diagnostic level of certainty with regard to Alzheimer's disease.